This invention relates to novel salts of 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid, a process for their preparation and their use in pharmaceutical compositions.
International patent application PCT/EP2011/062028 (WO2012/007539) discloses certain heterocyclic compounds that are active IP receptor agonists and their use in treating various conditions or diseases affected by the activation of the IP receptor, including, for example, pulmonary arterial hypertension. One of those heterocyclic compounds is 7-(2,3-di-p-tolyl-7,8-dihydropyrido-[2,3-b]pyrazin-5(6H)-yl)heptanoic acid, which has the following structure:

International patent application PCT/EP2011/062028 (WO2012/007539) discloses a process for preparing 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid and the corresponding mesylate salt.
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy leading to right ventricular hypertrophy. Exogenous administration of an agonist of the IP receptor has become an important strategy in the treatment of PAH. (See, e.g., Tuder et al., Am. J. Respir. Crit. Care. Med., 1999, 159: 1925-1932; Humbert et al, J. Am. Coll. Cardiol., 2004, 43:13 S-24S; Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619; McLaughlin et al, Circulation, 2006, 114:1417-1431; Rosenkranz, Clin. Res. Cardiol., 2007, 96:527-541; Driscoll et al, Expert Opin. Pharmacother., 2008, 9:65-81.).
A preferred route of administration of salts of 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid in the treatment of pulmonary arterial hypertension is pulmonary delivery by inhalation.
The free form of 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid has physical properties, including poor solubility and stability, that give rise to significant technical problems when manufacturing and formulating it for use as a pharmaceutical, particularly as an inhalable product, for example an inhalable dry powder.
The mesylate salt form of 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid is undesired mainly for toxicological reasons, not in respect of pure methanesulfonate (mesylate) salts, but rather for certain corresponding sulfonic acid esters that are known to exert genotoxic effects. Such esters can be formed during the synthesis of the drug substance or during the crystallization of the salt, or during storage, especially if the crystallization solvent contains alcohols, such as methanol, ethanol or propanol. They can also be formed when alcoholic solvents are used for the preparation of the dosage form.
It has now been found that at least some of issues can be overcome by preparing certain novel salts of 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid or at the very least such salts provide useful alternatives to the free form and the mesylate salt form.